1. Technical Field of the Invention
The present invention relates to the field of diagnosing or prognosticating neuropsychiatric diseases (hereinafter ND), eating disorders (hereinafter ED) or metabolic diseases. Eating disorders belong to motivational behavior disorders (MBD). The present invention also relates to the treatment of eating disorders. More particularly, the invention relates to a method for diagnosing or prognosticating NDs or EDs by measuring the affinity of a patient's autoantibodies for the biological molecule. The development of such invention follows the finding by the inventors of the psychological part in homeostasis and behavior of autoantibodies directed against certain biological molecules in particular neuropeptides, hormones and neurotransmitters.
“Autoantibodies” (hereinafter AutoAbs), in the sense of the present invention, means immunoglobulin capable of binding with molecules belonging to an organism producing said immunoglobulin. Such AutoAbs react against the “self”. An individual's self is defined as the assembly of molecules resulting from the normal expression of his or her genome. Such AutoAbs are naturally produced in the organism, i.e. they are not administrated by a passive immunization with human or animal original serum or with compounds containing monoclonal or recombinant antibodies. Such AutoAbs are not stimulated by an active immunization in which antigen is represented by neuropeptides, hormones or fragments thereof.
“Motivational behavior” means any behavior which serves to maintain the homeostasis of the organism by protecting it against external stresses or noxious modifications in environmental conditions. The motivational behavior is essentially involved in the regulation of nutrient intakes and is also used for extending life through reproduction. More exactly, motivational behavior includes the following behaviors: dietary intake, water intake, reproduction behavior which includes sexual and maternal or paternal behavior, defense or aggression behavior, exploration behavior, storage behavior and the behavior aiming at maintaining the body temperature and sleep. Such behaviors are regulated and integrated in a region of the brain called hypothalamus, since the alteration in the mechanism of a behavior also affects the others. In addition, strong connections of the hypothalamus with regions of the brain which are responsible for the emotional response, more particularly the rhinencephalon, also involve emotional disorders when one or several mechanisms of the motivational behavior is/are affected.
Some NDs or MBDs can be characterised by the presence of somatic and psychiatric symptoms. This can be explained by the neuro-anatomic interactions and also neuro-chemical interactions. Some NDs or MBDs can be distinguished, in which the psychiatric component is substantially characterised by symptoms involving modifications in the motivational behavior and/or emotion. Among NDs or MBDs with a strong psychiatric component, more particularly EDs, anxiety, depression, social phobia, delinquency, sexual disorders and sleep disorders can more particularly be mentioned.
Other NDs or MBDs can be characterised by the dominant alteration of the somatic component. This is most often revealed as pains which can be transitory or chronic such as for example in fibromyalgy or the irritable bowel syndrome. An important group of NDs or MBDs with strong somatic or psychiatric components is formed by EDs where somatic symptoms are associated with nutrient disorders. Undernutrition can more particularly be cited in anorexia nervosa or the case of obesity in bulimic behaviors.
In EDs, the psychiatric component can be characterised by symptoms affecting the motivational behavior and/or emotion such as dietary intake disorders and anxiety. The mechanisms implied in some NDs or EDs can also be involved in the occurrence of metabolic complications which can justify the inclusion of some metabolic diseases in the field of the invention, more particularly obesity for example, obesity due to excessive caloric intake, complications caused by obesity, type II diabetes and the metabolic syndrome.
2. Prior Art
Today, MBDs are an important public health issue, since the prevalence of anorexia nervosa is estimated between 0.3% to 0.7%, that of bulimia at about 3 to 5% in women, since EDs affect men 10 to 20 times less frequently. This would thus represent over 100,000 anorectic persons and over one million bulimic persons in France. Mortality due to anorexia nervosa can reach 10%. This affection is thus clearly extremely serious.
Besides, the persistence of pathologic symptoms and the frequent relapses noted in all the forms of EDs significantly reduce the quality of life of the affected persons. Other NDs and MBDs than those mentioned above are also extremely frequent in the world. As an example, mood disorders and anxiety affect altogether over 60 million persons in Europe (Andin-Sobocki and al., 2005).
So far, the origin of NDs and EDs or MBDs remains unknown or at least extremely argued about. On the other hand, no biological marker of such NDs or EDs is known which does not make it possible to have a specific diagnostic of NDs, EDs or MBDs. This is the reason why the present diagnosis of NDs, EDs and MBDs is purely symptomatic which is not always true. As regards the field of therapy, there is no etiologic treatment of EDs and clinical studies show the failures of traditionally prescribed drugs for NDs for example that on the antidepressive drug fluoxetine (Walsh and al., 2006).
In spite of such diagnosis and therapeutic problems, experimental research has made significant progress in the understanding of the molecular basis of motivational of behavior and emotion. Studies on the animal models showed the important part of neuropeptides and hormones, molecules synthesized by neuronal cells and endocrine cells respectively, in the physiological regulation of the motivational behavior and emotion (de Wied, 1969). This research made it possible to establish that some neuropeptides/hormones are preferably involved in motivational behavior, emotion or homeostasic functions (Hökfelt and al., 2003; Swaab, 2004). It was shown, for example, that vasopressin plays a key role in social dominance, fear and depression (Sewards and Sewards, 2003; Scantamburlo and al., 2005), ocytocin in inter-individual relationship and pain, adrenocorticotropic hormone in aggression, memory and depression (Haller and al., 2005), hypocretin in dietary intake and sleep (De Lecea and al., 1998), and neuropeptide Y in reproduction and dietary intake (Pedrazzini and al., 2003).
As regards energetic homeostasis, studies showed that the alpha-melabocyte/stimulating hormone (α-MSH or a-MSH or alpha-MSH) plays a key role in the regulation of eating behavior (Fan and al., 1997; Cone, 2005) and is an anorexiant. Besides, AgRP (Agouti related protein) plays the role of an antagonist of α-MSH through its competition for the same receptor of the melanocortin type, the stimulation of which by α-MSH appears as the final common channel to the induction of saturation (Cone, 2005). The other transmitters which are capable of modifying the dietary intake, for example monoamines (Leibowitz and Alexander, 1998; Meguid and al., 2000) interact at several levels with the system of melanocortin. Thus, this final channel appears to be critical for anorexiant actions of serotonin (Heisler and al., 2002), leptin (Seeley and al., 1997; Marsh and al., 1999; Choi and al., 2003; Zhang and Scarpace, 2006) insulin (Obici and al., 2001), pro-inflammatory cytokine (Lawrence and Rothwell, 2001; Marks and al., 2001), but also for the orexigenic action of ghrelin via neuropeptide Y (NPY) and AgRP. However, in spite of the progress of fundamental research, the pathologic mechanism involving neuropeptides in the pathogenesis of NDs and MBDs and more particular EDs is not clear.
A new hypothesis relating to the pathologic mechanism in which NDs or MBDs or EDs originate has recently been proposed (Fetissov and Hökfelt, 2003). According to this assumption, NDs or MBDs and EDs could be caused by the presence of circulant autoantibodies directed against neuropeptides/hormones more particularly implied in the regulation of the motivational behavior and emotion, more particularly alpha-melanocyte stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), the luteinizing hormone releasing hormone (LHRH), ocytocin and vasopressin (Fetissov and al., 2002; Fetissov and al., 2005). Recent studies also show the presence of autoantibodies against hypocretin neuropeptide during sleep disorders but in a way which is not different from that of control patients (Black and al., 2005; Tanaka et al., 2006). Other works showed in controlled patients and bulimic patients the presence of autoantibodies directed against the molecules which, through their chemical structure, do not belong to neuropeptides, but are involved in neurotransmission such as serotonin and dopamine as well as against the enzyme responsible for the synthesis of noradrenalin, dopamine β-hydroxylase (Corcos and al., 1999).
The presence of such autoantibodies in patients revealed in these works could suggest a pathological mechanism for NDs or MBDs and EDs, for example through the neutralization of messenger molecules. However, such antibodies have also been detected in sound persons, sometimes with higher titers than in sick persons (Corcos and al., 1999; Black and al., 2005; Fetissov and al., 2005). Thus, the detection of such autoantibodies for the diagnosis of NDs or EDs and MBDs does not seem to be a reliable method. Thus, so far, the real involvement of such autoantibodies in the etiopathogenia of NDs or MBDs and EDs is still not solved. Thus, there is a need for reliable and reproducible methods for diagnosing and prognosticating NDs or MBDs and EDs.